In–vitro Versuche zur Entfernbarkeit von Furansäure, Indoxylsulfat und Pentosidin im Plasma von chronischen Hämodialysepatienten mittels Albumindialyse

Da es bei Patienten mit chronischem Nierenversagen unter konventioneller Hämodialyse zur Akkumulation von urämischen, albumingebundenen Toxinen kommt, wurde in dieser Arbeit die Entfernbarkeit der Urämietoxine Furansäure (CMPF), Indoxylsulfat und Pentosodin mittels Albumindialyse geprüft. Dazu wurden In-vitro-Kreislaufversuche mit konventioneller Hämodialyse und Albumindialyse durchgeführt. Dabei zeigte sich, dass die stark albumingebundenen Toxine Furansäure (CMPF) und Indoxylsulfat durch die Albumindialyse signifikant besser entfernt wurden als durch die konventionelle Hämodialyse

Polyandrous females avoid costs of inbreeding

Why do females typically mate with more than one male? Female mating patterns have broad implications for sexual selection, speciation and conflicts of interest between the sexes, and yet they are poorly understood. Matings inevitably have costs, and for females, the benefits of taking more than one mate are rarely obvious. One possible explanation is that females gain benefits because they can avoid using sperm from genetically incompatible males, or invest less in the offspring of such males. It has been shown that mating with more than one male can increase offspring viability, but we present the first clear demonstration that this occurs because females with several mates avoid the negative effects of genetic incompatibility. We show that in crickets, the eggs of females that mate only with siblings have decreased hatching success. However, if females mate with both a sibling and a non-sibling they avoid altogether the low egg viability associated with sibling matings. If similar effects occur in other species, inbreeding avoidance may be important in understanding the prevalence of multiple mating

A time-space window between Eocene karst bauxite genesis and the first molasse deposition in the Dinaric Foreland Basin in the North Dalmatia, Croatia

Karst bauxite deposits in the North Dalmatian piggyback basin (NDPGB) are a part of the Mediterranean bauxite belt, which is the largest European bauxite deposit zone; however, there is a general lack of information regarding the genesis, age, and precursor of the bauxite deposits in this region. In this study, we combined detrital zircon U–Pb geochronology with compositional, mineralogical, and morphological data from four bauxite locations in the NDPGB to provide a new palaeogeographical and palaeoenvironmental evolution model for the Lutetian–Rupelian timeframe of the NDPGB. The Eocene climatic conditions began with the Palaeocene–Eocene Thermal Maximum event (∼56 Ma), followed by the Early Eocene Climatic Optimum (∼49 Ma) and Middle Eocene Climatic Optimum (∼40 Ma), and were completed as a cooling trend culminating around the Eocene/Oligocene boundary (∼34 Ma), with a shift towards an icehouse climate. These events were coeval with the continuous drift of the African continent towards Eurasia and the subsequent closure of the western part of the former Neo-Tethys Ocean associated with massive volcanic activity. Based on the bauxite deposits of the NDPGB, Early Eocene limestones formed in the last phase of the long-lasting Adriatic Carbonate Platform. The Middle Eocene orogenic activity resulted in an elevation in this area. High average temperatures, accelerated hydrological cycles and precipitation, and intensive continental weathering with increased volcanic carbon input resulted in favourable conditions for the development of karst bauxites at this time. Further Upper Eocene tectonic deformation of the NDPGB area resulted in the development of bauxite traps and enabled redeposition of the initial bauxite material. Subsequently, the bauxite deposits were covered with clastic carbonate molasse derived from the intensive erosion of the young Dinaric orogeny. The implications of this study are as follows. First, it provides new information on the timing of bauxitisation in the area by providing the first radiometric zircon geochronology, which refined and restricted the time window for bauxite formation in this region. Additionally, our results provide a new perspective on the possibility of aeolian precursors in karst bauxite formation and provide new constraints on the first tectonic marks of the initial Dinaric orogeny

A time-space window between Eocene karst bauxite genesis and the first molasse deposition in the Dinaric Foreland Basin in the North Dalmatia, Croatia

Karst bauxite deposits in the North Dalmatian piggyback basin (NDPGB) are a part of the Mediterranean bauxite belt, which is the largest European bauxite deposit zone; however, there is a general lack of information regarding the genesis, age, and precursor of the bauxite deposits in this region. In this study, we combined detrital zircon U–Pb geochronology with compositional, mineralogical, and morphological data from four bauxite locations in the NDPGB to provide a new palaeogeographical and palaeoenvironmental evolution model for the Lutetian–Rupelian timeframe of the NDPGB. The Eocene climatic conditions began with the Palaeocene–Eocene Thermal Maximum event (∼56 Ma), followed by the Early Eocene Climatic Optimum (∼49 Ma) and Middle Eocene Climatic Optimum (∼40 Ma), and were completed as a cooling trend culminating around the Eocene/Oligocene boundary (∼34 Ma), with a shift towards an icehouse climate. These events were coeval with the continuous drift of the African continent towards Eurasia and the subsequent closure of the western part of the former Neo-Tethys Ocean associated with massive volcanic activity. Based on the bauxite deposits of the NDPGB, Early Eocene limestones formed in the last phase of the long-lasting Adriatic Carbonate Platform. The Middle Eocene orogenic activity resulted in an elevation in this area. High average temperatures, accelerated hydrological cycles and precipitation, and intensive continental weathering with increased volcanic carbon input resulted in favourable conditions for the development of karst bauxites at this time. Further Upper Eocene tectonic deformation of the NDPGB area resulted in the development of bauxite traps and enabled redeposition of the initial bauxite material. Subsequently, the bauxite deposits were covered with clastic carbonate molasse derived from the intensive erosion of the young Dinaric orogeny. The implications of this study are as follows. First, it provides new information on the timing of bauxitisation in the area by providing the first radiometric zircon geochronology, which refined and restricted the time window for bauxite formation in this region. Additionally, our results provide a new perspective on the possibility of aeolian precursors in karst bauxite formation and provide new constraints on the first tectonic marks of the initial Dinaric orogeny

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Sociodemographic Disparities in the Receipt of Adjuvant Chemotherapy Among Patients With Resected Stage I–III Pancreatic Adenocarcinoma

Background: Adjuvant therapy for resected pancreatic adenocarcinoma was given a category 1 NCCN recommendation in 2000, yet many patients do not receive chemotherapy after definitive surgery. Whether sociodemographic disparities exist for receipt of adjuvant chemotherapy is poorly understood. Methods: The National Cancer Database was used to identify patients diagnosed with nonmetastatic pancreatic adenocarcinoma who underwent definitive surgery from 2004 through 2015. Multivariable logistic regression defined the adjusted odds ratio (aOR) and associated 95% CI of receipt of adjuvant chemotherapy. Among patients receiving chemotherapy, multivariable logistic regression assessed the odds of treatment with multiagent chemotherapy. Results: Among 18,463 patients, 11,288 (61.1%) received any adjuvant chemotherapy. Sociodemographic factors inversely associated with receipt of any adjuvant chemotherapy included uninsured status (aOR, 0.61; 95% CI, 0.50–0.74), Medicaid insurance (aOR, 0.66; 95% CI, 0.57–0.77), and lower income (P<.001 for all income levels compared with ≥$46,000). Black race (aOR, 0.72; 95% CI, 0.57–0.90) and female sex (aOR, 0.75; 95% CI, 0.65–0.86) were associated with lower odds of receiving multiagent chemotherapy. There was a statistically significant interaction term between black race and age/comorbidity status (P=.03), such that 26.4% of black versus 35.8% of nonblack young (aged ≤65 years) and healthy (Charlson-Deyo comorbidity score 0) patients received multiagent adjuvant chemotherapy (P=.006), whereas multiagent adjuvant chemotherapy rates were similar among patients who were not young and healthy (P=.15). Conclusions: In this nationally representative study, receipt of adjuvant chemotherapy appeared to be associated with sociodemographic characteristics, independent of clinical factors. Sociodemographic differences in receipt of adjuvant chemotherapy may represent a missed opportunity for improving outcomes and a driver of oncologic disparities

Mature dendritic cells boost functionally superior CD8(+) T-cell in humans without foreign helper epitopes

We have recently shown that a single injection of mature, antigen-pulsed, human dendritic cells (DCs) rapidly elicits CD4(+) and CD8(+) T-cell immunity in vivo. The DCs were pulsed with 2 foreign proteins, keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT), as well as an HLA A2.1-restricted influenza matrix peptide (MP). Responses to all 3 antigens peaked at 30–90 days after immunization and declined thereafter. To determine if the foreign helper proteins (TT and KLH) were essential for CD8(+) T-cell responses to the viral peptide, we reinjected 3 of the HLA-2.1 subjects with mature DCs pulsed with MP alone. All 3 volunteers showed a rapid boost in MP-specific immunity, and freshly sampled blood from 1 contained cytolytic T cells. In all 3 subjects, CD8(+) T-cell responses to booster DCs were faster and of greater magnitude than the responses to the first DC injection. Importantly, the T cells that proliferated after booster DC treatment secreted interferon-γ upon challenge with much lower doses of viral peptide than those elicited after the first injection, indicating a higher functional avidity for the ligand. These data begin to outline the kinetics of T-cell immunity in response to DCs and demonstrate that booster injections of mature DCs enhance both qualitative and quantitative aspects of CD8(+) T-cell function in humans. This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org. J. Clin. Invest. 105:R9–R14 (2000)

Retroperitoneal teratoma with somatic malignant transformation: A papillary renal cell carcinoma in a testicular germ cell tumour metastasis following platinum-based chemotherapy

BACKGROUND: Malignant transformation describes the phenomenon in which a somatic component of a germ cell teratoma undergoes malignant differentiation. A variety of different types of sarcoma and carcinoma, all non-germ cell, have been described as a result of malignant transformation. CASE PRESENTATION: A 33-year-old man presented with a left testicular mass and elevated tumour markers. Staging investigations revealed retroperitoneal lymphadenopathy with obstruction of the left ureter and distant metastases. Histopathology from the left radical orchiectomy showed a mixed germ cell tumour (Stage III, poor prognosis). The ureter was stented and four cycles of cisplatin, etoposide and bleomycin chemotherapy administered. After initial remission, the patient recurred four years later with a large retroperitoneal mass involving the renal vessels and the left ureter. Left retroperitoneal lymph node dissection with en-bloc resection of the left kidney was performed.Histopathology revealed a germ cell tumour metastasis consisting mainly of mature teratoma. Additionally, within the teratoma a papillary renal cell carcinoma was found. The diagnosis was supported by immunohistochemistry showing positivity for AMACR, CD10 and focal expression of RCC and CK7. There was no radiological or histo-pathological evidence of a primary renal cell cancer. CONCLUSIONS: To the best of our knowledge, malignant transformation into a papillary renal cell carcinoma has not been reported in a testicular germ cell tumour metastasis following platinum-based chemotherapy. This histological diagnosis might have implications for potential future therapies. In the case of disease recurrence, renal cell cancer as origin of the recurrent tumour has to be excluded because renal cell carcinoma metastases would not respond well to the classical germ cell tumour chemotherapy regimens